Cancer or malignancy is the result of uncontrolled growth of a given cell type that occurs together with invasion of the surrounding tissue and the spread of malignant cells. Molecular evidence suggests the important roles for PI3 signaling pathway in tumor promotion and progression (Nature Rev. Drug Discovery 2005, 4, 988-1003).
References may be made to Journal “Nature Rev. Drug Discovery 2005, 4, 988-1003PI3” wherein signaling pathway abnormalities are common in many cancers regardless of their origin, for example breast, prostate, pancreas, acute lymphoblastic leukemia, chronic myelogenous leukemia. Therefore, inhibition of PI3 signaling pathway by molecules is an efficient approach for the development of novel drugs for treating diseases such as cancers of different origin.
PI3 inhibitors have anticancer properties. For example, Wortmannin and LY 294002 have antitumor activity in vitro and in vivo, and sensitize tumor cells to other targeted therapeutics, chemotherapy and radiation (Clin. Cancer Res. 1997, 3, 1149-1156; Clin. Cancer Res. 2001, 7, 3269-3275; Leuk. Res. 2000, 24, 917-925; Cancer Res. 2002, 62, 1087-1092).
High levels of intracellular nitric oxide (NO) production cause S-nitrosylation of a number of proteins leading to cell death (Nature Cell Biology 2005, 7, 645-646).
Hydroxychavicol is known to induce cell cycle arrest and apoptosis in oral KB carcinoma cell line (Cell. Mol. Life Sci., 2004, 61, 83-96) and in hepatocarcinoma cells (Cancer lett., 2000, 155, 29-35). Hydroxychavicol has anti-oxidative property inducing cell-cycle arrest and apoptosis of oral KB carcinoma cells (British Journal of Pharmacology, 2002, 135, 619-630), anti-mutagenic property against tobacco-specific carcinogens (Mutat. Res., 1989, 210,249-253), as well as chemopreventive activity against benzo[a]pyrene induced forestomach tumors in mice (J. Ethnopharmacol., 1991, 34, 207-213). Conflicting literature exists on the effect of hydroxychavicol on cycloxygenase 2: while one report suggested enhancement of expression (J. Oral Pathol. Med., 2003, 32, 522-529), another report suggested hydroxychavicol-mediated inhibition of platelet aggregation by suppression of cyclooxygenase, thromboxane production and calcium mobilization (British Journal of Pharmacology, 2007, 152, 73-82). Hydroxychavicol is a potent COX-1/COX-2 inhibitor and could be potentially used in prevention or treatment of cardiovascular disease through its anti-inflammatory effect (British Journal of Pharmacology, 2007, 152, 73-82). The chemopreventive efficacy of betel leaf extract and its constituents, including hydroxychavicol on 7,12-dimethylbenz(a)anthracene induced skin tumors in mouse, has been reported (Indian Journal of Experimental Biology, 1991, 29, 346-351). The anti-mutagenic and anti-carcinogenic properties of hydroxychavicol and eugenol have been reported (Mutagenesis, 1989, 4, 200-204). Another recent report suggested that allylpyrocatechol (hydroxychavicol) inhibitied NF-κB pathway in lipopolysaccharide (LPS)-induced macrophages leading to suppression of iNOS, interleukin-12 and TNF-α (International Immunopharmacoloty, 2008, 8, 1264-1271).
The present invention relates to inhibition of prosurvival pathway PI3-Akt. The phosphatidylinositol-3-kinase (PI3)/AKT signaling pathway is crucial to many aspects of cell growth and survival. The PI3/Akt pathway is activated in cancer (Nature Reviews Drug Discovery, 2005, 4, 988-1003) making this pathway an optimal target for cancer therapy. The present invention also relates to production of NO (nitric oxide) by hydroxychavicol in cancer cells. Experiments with siRNAs identified endothelial nitric oxide synthase (eNOS) as the producer of hydroxychavicol mediated NO.
Hydroxychavicol has some inherent problem of arial autooxidation leading to production of super oxide and hydrogen peroxide (Mutation Research, 2004, 565, 35-44). Autooxidation makes this molecule very unstable. We therefore prepared some derivatives of hydroxychavicol which lack autooxidation potential making the molecules more stable. At the present time, the inventors are not aware of any prior arts that discloses that hydroxychavicol or its derivates inhibit PI3 signaling pathway and or induce nitric oxide in cancer cells.